Current status of the development of dengue vaccines

Abstract

Dengue fever is caused by the mosquito-borne dengue virus (DENV), which is endemic in more than 100 countries. Annually, there are approximately 390 million dengue cases, with a small subset manifesting into severe illnesses, such as dengue haemorrhagic fever or dengue shock syndrome. Current treatment options for dengue infections remain supportive management due to the lack of an effective vaccine and clinically approved antiviral. Although the CYD-TDV (Dengvaxia®) vaccine with an overall vaccine efficacy of 60 % has been licensed for clinical use since 2015, it poses an elevated risk of severe dengue infections especially in dengue-naïve children below 9 years of age. The newly approved Qdenga vaccine was able to achieve an overall vaccine efficacy of 80 % after 12 months, but it was not able to provide a protective effect against DENV-3 in dengue naïve individuals. The Butantan-DV vaccine candidate is still undergoing phase 3 clinical trials for safety and efficacy evaluations in humans. Apart from live-attenuated vaccines, various other vaccine types are also currently being studied in preclinical and clinical studies. This review discusses the current status of dengue vaccine development.

Keywords: Dengue virus; Flavivirus; Live-attenuated vaccine; Vaccine; Vaccine development.

Fig. 1

Schematic illustration of the types of ADE mechanisms. (A) Extrinsic ADE involves an increased uptake of viruses into phagocytic cells via the Fc gamma receptors, leading to increased viral replication. (B) Intrinsic ADE involves complement activation by the formation of virus-non-neutralizing antibody complexes, which caused virus-tolerant states, increased inflammation, and immunopathology. The original figure was created using Biorender software.

Fig. 2

Potential impact of original antigenic sin of T cells on DENV-specific T cell responses during a secondary DENV infection. During a primary infection (e.g. with DENV-1), there is an expansion of naïve T cells with high avidity for serotype-specific DENV-1 epitopes. These T cells undergo optimal T cell receptor triggering, which lead to the production of IFN-γ and CD107a, resulting in the efficient lysis of DENV-infected cells. In the event of a secondary infection with a heterologous serotype (e.g. DENV-2), cross-reactive memory T cells specific for the primary infecting virus, DENV-1, dominate the response due to their increased numbers and their lower activation threshold as compared to naïve T cells. Some of these cells may have a lower avidity for DENV 2 antigens, which result in suboptimal T cell receptor triggering and subsequent production of high levels of TNF-α and low levels of CD107a and IFN-γ, leading to an inefficient lysis of DENV-infected cells. Secretion of high amounts of TNF-α may contribute to the cytokine storm and plasma leakage. The original figure was created using Biorender software.

Fig. 3

Types of dengue vaccines. The original figure was created using Biorender software.

Fig. 4

Schematic representation of the developmental strategies of the three live-attenuated dengue vaccines. The backbone of the CYD-TDV/Dengvaxia vaccine consists of the YF-17D vaccine strain and the prM and E genes of YF-17D were replaced with those of the four DENV serotypes. The TAK-003/Qdenga vaccine consists of the live-attenuated DENV-2 PDK-53 strain (TDV-2) as the backbone and the DENV-2 prM and E genes are substituted with those from DENV-116007 (TDV-1), DENV-316562 (TDV-3), and DENV-41036 (TDV-4). The TV003/TV005/Butantan-DV vaccine is developed via the creation of a series of attenuated DENV with introductions of 30 nucleotide deletions in the 3’-UTR and mutations in the NS proteins. Grey = YF-17D virus, red = DENV-1, yellow = DENV-2, green = DENV-3, blue = DENV-4, the black triangle represents the mutations at the 3’-UTR. The figure was created using Biorender software. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)